Patients undergoing chemotherapy or radiotherapy for treatment of malignancies are almost invariably faced with moderate or severe side effects due to their therapy. One of the common side effects faced by cancer patients is the induction of ulcerative mucositis of the mucosal membranes. This mucositis is especially prominent in the oral cavity. This side effect, although not as life threatening as other side effects such as anemia or immunosuppression, nonetheless often becomes the dose limiting factor in the continuation of therapy in many cancer patients.
Ulcerative mucositis is marked by the formation of slowly healing open ulcers in the oral cavity causing a great deal of pain and discomfort to the patient. Eating, drinking, and swallowing become difficult and painful and additionally, the salivary glands are often effected compounding the discomfort. The presence of open ulcers in the mouth often lead to opportunistic infections of bacterial, viral, and fungal origin in these patients, who are often immunologically suppressed due to their therapy. These oral infections must be carefully monitored to avoid their spreading to life-threatening, systemic infections.
As yet, there is no treatment for such mucositis except either cessation of the therapy or palliative and supportive interventions. Some of the palliative treatments in current use include the use of antibiotics to reduce the chance of infection, the use of anti-histamines and anti-inflammatory drugs, and the use of pain reducing medications. All of these treatments are either unacceptable, as with the case of cessation of cancer therapy or partially successful in relieving the suffering from the mucositis.
For a more detailed description of radio- and chemotherapy induced mucositis, its treatment, management, and causes see Holland, J. F. et al.; Cancer Medicine, Third Ed., Lea & Febiger, Philadelphia Pa., 1993; Vol.2, Section XL, pp. 2382-2385 and references therein.
The current understanding of the mechanism which causes ulcerative mucositis in cancer patients undergoing radio- or chemotherapy is that both normal mucosal cells and malignant cancer cells share one common property, i.e., these are cells which are rapidly growing or cycling. Normally the mucosal lining turns over at a very rapid rate compared to most other tissue compartments in the body. This rapid mucosal turnover is also shared by several other normal tissues such as cellular blood elements, hair, skin, etc. It is not surprising to find that these tissues are also targets of various cancer therapies, because the governing strategy for the treatment of cancer has been aimed at targeting rapidly proliferated cancer cells by a variety of cellular mechanisms. Thus, cancer drugs which are most effective at interrupting the growth of cancer cells are often the most damaging agents to the normal, proliferating cells in the body, such as the mucosal lining. Other tissue compartments of the body whose cells are not as rapidly cycling, such as muscle and nerve cells, are not as prone to the rapid and deleterious effects of such cancer therapies.
Recently there has been a report in the literature, suggesting that Transforming Growth Factor-.beta. 3 (TGF-.beta. 3) may be useful in treating patients suffering from ulcerative mucositis induced by cancer therapy. The authors hypothesis is that TGF-.beta. 3 slows the rate of turnover of epithelial cells (epithelial cells are the predominant cell type in the mucosal lining) and thus these cells might be spared the effects of the cancer therapy. The authors give experimental data both in cell culture and in animal models which support their hypothesis. (Sonis, et al., Prevention Of Chemotherapy-Induced Ulcerative Mucositis by Transforming Growth Factor-.beta. 3., Abst., NIH Symposia on TGF-.beta.s, Bethesda Md., 3 May 1994).
TGF-.beta. is a peptide growth factor which refers to a generic family of peptides, often called isoforms meaning that members of the family either share amino acid homology and/or have similar physiological actions. Of particular interest to the subject of wound healing are: TGF-.beta.s 1, 2, and 3. For further discussion of the TGF-.beta. family of peptides, the subject is reviewed in: Roberts et al., The transforming growth factor-.beta.s. In: Sporn and Roberts, eds. Peptide growth factors and their receptors I. Berlin: Springer Verlag, 1990: 419-472.
It would seem reasonable that an agent which might slow the rapid rate of turnover of the mucosal lining may be useful in protecting that tissue from the effects of the commonly used cancer therapies.